SMALL MOLECULE DRUG DEVELOPMENT SHARED RESOURCES PROJECT SUMMARY/ABSTRACT The Small Molecule Drug Development Shared Resource (Drug Development SR) was established in September 2015 to address the lack of critical infrastructure enabling small molecule screening and the identification of small-molecule probes. The mission of the Drug Development SR is to enable investigators to optimize robust assays in 384-well format and to screen these assays across large chemical libraries to identify new small molecules that may be the starting point for innovative cancer therapeutics. In the first year, a wide range of investigators from Case Western Reserve University (CWRU), University Hospitals (UH), Cleveland Clinic (CC), a collaborator from Duke University, and a Cleveland biotech startup utilized the Drug Development SR, testifying to the large demand for small-molecule screening. Since its establishment, the Drug Development SR has worked with 17 investigators, approximately 65% of whom are Case CCC members, accounting for 79% of total usage, and representing 4 of the 7 Case CCC Programs. The Specific Aims of the Small Molecule Drug Development Shared Resource are to: 1. Provide assay development and high-throughput screening services, using both high-throughput and high- content approaches to screen libraries of known bioactive compounds (bioactives) and diverse screening libraries. 2. Share expertise to design and optimize robust high-throughput assays tailored to specific projects, by consultation between the PI, the Director, and the Managing Director to inform project design, execution, and troubleshooting. 3. Train new users, including PIs, research scientists, and trainees, in proper and safe operation of the SR's automation equipment at reasonable cost, and welcome/include their participation during assay development and execution. 4. Offer advice and guidance to advance hits to leads using cheminformatics and medicinal chemistry, by providing recommended strategies for prioritizing hits, and linking investigators with medicinal chemists. 5. Guide users toward SRs and potential collaborating investigators in Case CCC Programs with complementary capabilities relevant to drug development as projects evolve, including connections to researchers with expertise in proteomics, in vitro and in vivo pharmacology, and in vivo testing. Moving forward, the Drug Development SR aims to complete 3 or more full high-throughput screens per year and 6 or more pilot screens to maintain a pipeline of robust assays for future large-scale screens. Additionally, the facility will expand its equipment set to provide redundancy in several key instruments, and will expand its screening libraries to 100,000 small molecules to match typical screen sizes performed in other academic screening centers.